Project Summary/Abstract Obesity and type 2 diabetes mellitus (T2DM) have become national and global epidemics. The rising prevalence of obesity has dramatically increased the burden of dyslipidemia, specific types of cancer, nonalcoholic fatty liver disease, T2DM and cardiovascular diseases, the leading cause of mortality in the country. Recent studies have highlighted the intimate links between metabolic diseases and adipose tissue inflammation. Adipose inflammation plays an integral role in the development of metabolic syndrome. Adipose-immune interactions can have both positive and negative effects on adipose tissue homeostasis and whole body metabolism. What initiates adipocyte dysfunction and the inflammatory processes in obesity remain an enigma. This research proposal seeks to understand the molecular mechanisms that underlie adipocyte dysfunction and adipose inflammation. We identify fam20c as a novel regulator of adipose tissue inflammation and insulin resistance. Obesity induces expression of fam20c in adipocytes. Conversely, ablation of fam20c in adipocytes ameliorates hyperglycemia. In this proposal, we seek to assess the mechanistic links between insulin resistance and inflammation. We will pursue the following specific aims: 1. Determine the physiological and cellular mechanisms by fam20c regulates energy balance, glucose homeostasis and adipose tissue inflammation. 2. Dissect the molecular mechanism of action of the fam20c kinase in regulating inflammatory gene expression and insulin resistance. 3. We will test the hypothesis that adipose-specific ablation of fam20c can reverse established T2DM. The overall goal of these studies will shed light on how therapies directed against fam20c can be used to restore metabolic health in patients with T2DM.